Despite more than two decades of health literacy research, causal pathways linking health literacy to health outcomes have not been well-defined. The result has been continued controversy in the concept's definition and less-informed interventions attempting to either promote clear, actionable health communication or reduce literacy disparities in healthcare with variable success. The lead investigators (Paasche-Orlow & Wolf) have previously proposed a conceptual framework for health literacy. While it has been frequently cited in the literature, there have been limited opportunities to test and refine the underlying premises. Indeed, no conceptual model of health literacy to date has been empirically tested. Leveraging several unique and large datasets that include an expanse of relevant covariates, we propose rigorous secondary analyses to investigate proposed causal pathways linking health literacy to health outcomes including intermediary chronic disease outcomes, quality of life, hospitalization and mortality risk. In addition, we will specifically examine how health literacy may potentially serve a mediating role and in part explain certain known health disparities. Associations between low health literacy and worse outcomes will be mostly explained by inadequate knowledge, self-efficacy, services use, and self-care behavior. Low health literacy, numeracy, problem-solving, and knowledge with health behaviors will represent significant mediators of the relationship between race/ethnicity and worse clinical outcomes. Seven unique and diverse datasets in which the most common measures used in health literacy research (REALM, TOFHLA, NVS, others) and a rich array of additional key variables were measured. Structural equation modeling, meditational and meta-analytic techniques to determine causal pathways linking health-related literacy, numeracy, problem-solving, and knowledge with health behaviors, outcomes, and disparities will be used. Chronic disease (HbA1c, blood pressure, LDL cholesterol, asthma control) functional health status and quality of life cognitive function risk of hospitalization and mortality. The outcomes are an improved understanding of the causal mechanisms linking health literacy to health outcomes and the role of health literacy in explaining health disparities. This will be the most extensive investigation of its kind, and will significantly contribute to our understanding of the important factors inherent in defining health literacy and how best to respond to the problem. We will disseminate our findings on a Web site to promote transparency and allow continued modification of the model as further data become available.